0021-972X/03/$15.
00/0 The Journal of Clinical Endocrinology & Metabolism 88(12):5951–5956
Printed in U.S.A.
Pharmacokinetics and Dose Finding of a Potent
Aromatase Inhibitor, Aromasin (Exemestane), in
Young Males
NELLY MAURAS, JOHN LIMA, DEVAL PATEL, ANNIE RINI, ENRICO
AND BARBARA LIPPE
Nemours Children’s Clinic and Research Programs (N.M., J.L., A.R.), , Jacksonville, Florida 32207; and University of
Florida Health Sciences Center (D.P.) and Amersham Pharmacia Biotech (E.d.S., A.K., B.L.), Peapack, New Jersey 07977
Suppression of estrogen, via estrogen receptor or aromatase
blockade, is being investigated in the treatment of different
conditions. Exemestane (Aromasin) is a potent and selective
irreversible aromatase inhibitor. To characterize its suppres-
sion of estrogen and its pharmacokinetic (PK) properties in
males, healthy eugonadal subjects (14 –26 yr of age) were re-
cruited. In a cross-over study, 12 were randomly assigned to
25 and 50 mg exemestane daily, orally, for 10 d with a 14-d
washout period. Blood was withdrawn before and 24 h after
the last dose of each treatment period. A PK study was per-
formed (n ⴝ 10) using a 25-mg dose. Exemestane suppressed
plasma estradiol comparably with either dose [25 mg, 38% (P <
T HE BIOLOGICAL ACTIONS of estrogens in males have
begun to be unraveled via prismatic cases of estrogen
deficiency in adults (1–3), gene knockout experiments in
mice (4 – 6), and metabolic studies in vivo (7). Experiments in
both animals and humans, for example, have clearly shown
that epiphyseal fusion and the completion of final adult
height are processes regulated by estrogen, even in the male.
Male patients with functional mutations in either the estro-
gen receptor gene (1) or the aromatase gene (2, 3) have
demonstrated continued linear growth into adulthood, tall
stature, and osteopenia. This information has lead to the
investigation of pharmacologically induced estrogen defi-
ciency as an adjunct in delaying epiphyseal fusion in males
with short stature and potentially increasing final adult
height (8, 9).
The biosynthesis of estrogens from C19 steroids is regu-
lated by the aromatase cytochrome p450 (CYP19), a product
of a single CYP19 gene. This enzyme, which catalyzes the
conversion of androstenedione and testosterone to estrone
and estradiol, is widely expressed in numerous tissues, in-
cluding bone (10, 11). We have conducted detailed studies of
the metabolic effects of selective estrogen suppression in
young eugonadal males using anastrozole, a potent and se-
lective nonsteroidal aromatase inhibitor, and have shown
that specific blockade of the aromatase enzyme for 10 wk did
not have catabolic effects on protein metabolism, body com-
position, measures of muscle strength, and bone calcium
metabolism (7). The data suggest that estrogens do not con-
Abbreviations: AUC, Area under the curve; CBC, cell blood count;
HDL, high density lipoprotein; LDL, low density lipoprotein; PK,
pharmacokinetic.
5951
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Copyright © 2003 by The Endocrine Society
doi: 10.1210/jc.2003-031279
DI SALLE, AMBROSE KWOK,
0.002); 50 mg, 32% (P < 0.008)], with a reciprocal increase in
testosterone concentrations (60% and 56%; P < 0.003 for both).
Plasma lipids and IGF-I concentrations were unaffected by
treatment. The PK properties of the 25-mg dose showed the
highest exemestane concentrations 1 h after administration,
indicating rapid absorption. The terminal half-life was 8.9 h.
Maximal estradiol suppression of 62 ⴞ 14% was observed at
12 h. The drug was well tolerated. In conclusion, exemestane
is a potent aromatase inhibitor in men and an alternative to
the choice of available inhibitors. Long-term efficacy and
safety will need further study. (J Clin Endocrinol Metab 88:
5951–5956, 2003)
tribute significantly to the changes in body composition and
protein synthesis observed with changing androgen levels in
males. It also suggested that this level of aromatase inhibition
does not negatively impact markers of bone calcium metab-
olism, at least in the short term.
A new irreversible aromatase enzyme blocker, exemestane
(Aromasin), offers an alternative to suppress estrogen con-
centrations. It is structurally related to the natural substrate
androstenedione, and it is metabolized to an intermediate
that binds to the active site of the enzyme and inactivates it.
It is excreted in the urine and feces. It decreases estradiol
concentrations in postmenopausal women, but has no effect
on the synthesis of glucocorticosteroids or aldosterone (12,
13). All pharmacokinetic (PK) data available to date are from
postmenopausal women, as it is presently used in this pop-
ulation for the treatment of metastatic breast cancer (12–15).
A daily dose of 25 mg has been shown to have no effect on
circulating testosterone concentrations in females. This study
was designed with two aims: first, to investigate the dose of
exemestane that can be safely given in adolescent/young
adult males with minimal or no side-effects, and second, to
investigate the PK and pharmacodynamics of this aromatase
inhibitor in males.
Subjects and Methods
These studies were approved by the Nemours Children’s Clinic clin-
ical research review committee and Baptist Medical Center/Wolfson
Children’s Hospital institutional review board. Healthy lean male vol-
unteers between 14 –26 yr of age were recruited after giving informed
written consent to participate in study I or II (see below). Their clinical
characteristics are summarized in Table 1.
 5952 J Clin Endocrinol Metab, December 2003, 88(12):5951–5956
TABLE 1. Clinical characteristics of the study subjects
Study I Study II
(n ⫽ 12) (n ⫽ 10)
Race, n (%)
White 8 6
Black 1 1
Hispanic 3 1
Other 2 testosterone was measured by a validated gas chromatography/mass
Age (yr)
Mean ⫾ SD 18.8 ⫾ 3.5 19.4 ⫾ 3.8
Range 14.0 –25.0 14.0 –26.0
BMI (kg/m2)
Mean ⫾ SD 24.0 ⫾ 2.9 25.4 ⫾ 3.0
Range 20.0 –29.0 20.9 –29.1
Study I: dose finding
Two different doses of exemestane (Aromasin, 25-mg tablets) were
administered orally in random order for 10 d with a 14-d washout in
between. Twelve subjects were divided into 2 groups (treatment se-
quences): group I received 25 mg in period 1 and 50 mg in period 2, and
group II received 50 mg in period 1 and 25 mg in period 2. Blood was
withdrawn in the morning, between 0800 – 0900 h at the beginning of
each treatment cycle and 24 h after the last dose of each treatment cycle
(4 blood draws) for various pharmacodynamic assays. These included
estradiol, estrone, estrone sulfate, androstenedione, testosterone, free
testosterone, dehydroepiandrosterone sulfate, cortisol, SHBG, IGF-I,
IGF-binding protein-3, and plasma lipid profiles [triglycerides, total
cholesterol, high density lipoprotein (HDL) cholesterol, and low density
lipoprotein (LDL) cholesterol]. Safety data, including general chemis-
tries, cell blood count (CBC), urinalysis, and liver profiles, were mea-
sured as well. All adverse events were recorded.
Study II: PK study
Ten male volunteers participated in this study arm. They came to the
Clinical Research Center at 0700 h after an overnight fast. An iv heparin
lock was placed in a forearm vein for the blood drawing after numbing
the skin with a topical anesthetic (EMLA, AstraZeneca, Wilmington,
DE). In addition to safety laboratories (CBC, chemistry profile, and
urinalysis), blood was withdrawn for determining exemestane, its me-
tabolite 17-hydroexemestane, estradiol, testosterone, LH, and FSH con-
centrations. A regular breakfast was served that contained 30% of the
total calories as fat, and a single dose of 25 mg exemestane was given
with the meal. Blood was withdrawn at 0, 1, 2, 3, 4, 8, 12, 24, 48, 72, 144,
and 240 h after the administration of exemestane for the same assays as
at baseline. The subjects were fed a regular diet and were free to move
around. After the 24 h sample was withdrawn, subjects were discharged
home, and the 48, 72, 144, and 240 h samples were obtained as out-
patients. LH and FSH were only measured up to 24 h.
Assays
As exemestane is a steroid, to eliminate any confounding interference
of this compound and its metabolites on the assays of related endoge-
nous steroidal hormones (androgens and estrogens), careful separation
of the given compounds in the plasma samples was performed using
HPLC, followed by RIA, as described by Johannessen et al. (16). Plasma
estradiol, estrone, estrone sulfate, testosterone, and androstenedione
concentrations were measured by a validated HPLC-RIA method at
Aster-Cephac Laboratories (Saint-Benoit, Cedex, France). Briefly, a 2-ml
plasma sample was loaded onto Amprep C18 cartridge and the fraction
containing estrone sulfate or free steroids (estradiol, estrone, andro-
stenedione, and testosterone) were eluted with 4 ml 24% acetonitrile in
water or 100% acetonitrile, respectively. Estrone sulfate was hydrolyzed
with arylsulfatase, and the deconjugated estrone was further extracted
with a C18 cartridge. The extracted fractions were injected into a reverse
phase HPLC system. The eluates corresponding to estradiol, estrone,
androstenedione, and testosterone or to deconjugated estrone (to mea-
sure estrone sulfate) were collected and subjected to specific RIAs using
commercial kits. The collected fractions were evaporated and reconsti-
tuted using an assay buffer before RIA. Appropriate plasma samples,
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Mauras et al. • Pharmacokinetics of Exemestane in Males
spiked with each of the tritiated hormones, were included in each an-
alytical run to calculate overall recoveries to correct results measured by
RIA. All extractions were performed singly, and all RIA analysis were
performed in duplicate. The lower limit of sensitivity was 0.7 pg/ml for
estradiol, 1.8 pg/ml for estrone, 6 pg/ml for estrone sulfate, 40 pg/ml
for androstenedione, and 30 pg/ml for testosterone. The overall inter-
assay coefficients of variation were: estradiol, 6.2%; estrone, 12.9%; es-
trone sulfate, 8.2%; androstenedione, 12.6%; and testosterone, 8.6%. Free
spectrometry bioanalytical method at Taylor Technology, Inc. (Prince-
ton, NJ). LH and FSH were measured by RIA at the Nemours Biomedical
Research Laboratory using commercial kits from Diagnostic Systems
Laboratories, Inc. (Webster, TX). All other hormones were measured at
a contract laboratory by RIAs using commercial kits. All samples were
run in the same assay run. Concentrations of plasma lipids, chemistry
profile, and CBC were measured using automated analyzers at Baptist
Medical Center (Jacksonville, FL). Exemestane and 17-hydroexemestane
plasma levels were measured at Pharma Bio Research (Assen, The Neth-
erlands) using a validated liquid chromatography method with tandem
mass spectrometry detection (17). The lower limit of sensitivity was 0.1
ng/ml for both assays.
Statistical analysis
For the pharmacodynamic results of study I, descriptive statistics
were generated for the assays measured by group (sequence) and by
treatment. The mean concentrations at baseline and at the end of treat-
ment were summarized by period and by treatment group for all assays.
A paired t test was used to test the difference between baseline and day
10 concentrations for each assay. A cross-over ANOVA with factors for
period, treatment, group (sequence), and subject within group was con-
ducted (18). A baseline value was added to the model. A paired t test
was used to test the difference in concentrations at baseline and on d 10
for all assays. Significance was established at P ⬍ 0.05.
PK analysis
The PK of exemestane were determined by noncompartmental anal-
ysis (19) using the computer program WinNonlin (Pharsight Corp.,
Mountain View, CA). The maximum plasma concentration was the
highest concentration observed for each individual. The area under the
curve (AUC) was calculated using the linear trapezoidal rule up to
the last quantifiable concentration and extrapolated to infinite time
(AUC0-inf). The half-life of the terminal decay phase, t1/2,z, was deter-
mined by linear regression analysis of the natural log concentration vs.
time curve, where t1/2,z ⫽ ln2/Kel, where Kel is the slope of the regres-
sion line. Oral clearance was calculated as oral dose/AUC0-inf. Analo-
gous calculations were performed on (c ⫻ t) vs. time plots to estimate
the area under the first moment curve (AUMC0-inf). The mean residence
time was calculated as AUMC/AUC PK parameters were summarized
with descriptive statistics.
Results
Study I: dose finding
Analysis of the data on hormone concentrations after the
25- and 50-mg doses showed no difference in any of the
parameters measured due to an order effect; hence, the data
were grouped for analysis by dose. The 25- and 50-mg doses
of daily exemestane had comparable effects in suppressing
circulating estrogen concentrations, with 38 ⫾ 24% (mean ⫾
sd; P ⫽ 0.002 vs. baseline) and 32 ⫾ 29% (P ⫽ 0.008) decreases
in estradiol concentrations, 71 ⫾ 12% (P ⬍ 0.0001) and 74 ⫾
12% (P ⬍ 0.0001) decreases in estrone concentrations, and
45 ⫾ 27% (P ⫽ 0.004) and 51 ⫾ 20% (P ⫽ 0.02) decreases in
estrone sulfate concentrations after doses of 25 and 50 mg,
respectively. There was an increase in circulating testoster-
 Mauras et al. • Pharmacokinetics of Exemestane in Males
one concentrations after both 25 mg (60 ⫾ 58%; P ⫽ 0.001) and
50 mg (56 ⫾ 48%; P ⫽ 0.003) exemestane. Androstenedione
concentrations were increased as well after 25 mg (32 ⫾ 36%;
P ⫽ 0.004) and 50 mg (47 ⫾ 59%; P ⫽ 0.052) exemestane,
respectively (Fig. 1 and Table 2). SHBG concentrations were
decreased by 21 ⫾ 7% (P ⫽ 0.0003) and 19 ⫾ 39% (P ⫽ 0.18)
at 25 and 50 mg exemestane, respectively. Free testosterone
concentrations were increased by 117 ⫾ 74% (P ⫽ 0.0001) and
154 ⫾ 95% (P ⬍ 0.0001) at both doses, due to the decrease in
SHBG and the increase in total testosterone. No effect on
circulating dehydroepiandrosterone sulfate was observed at
either dose. Serum cortisol concentrations increased signif-
icantly (38 ⫾ 39%; P ⫽ 0.008) with the 25-mg dose, but not
the 50-mg dose, yet the increase was well within the normal
range of cortisol concentrations. Plasma IGF-I decreased sig-
nificantly (⫺13 ⫾ 11%; P ⫽ 0.008) after the 25-mg dose, but
FIG. 1. Estrogen and androgen plasma levels after 10 d of daily exemestane (25 or 50 mg) in healthy young males (mean ⫾ SD; n ⫽ 9 –11). To
convert to Systeme International units: estradiol, picomoles per liter (⫻3.671); estrone, picomoles per liter (⫻3.699); androstenedione, nanomoles
per liter (*0.003492); and testosterone, nanomoles per liter (⫻0.03467).
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J Clin Endocrinol Metab, December 2003, 88(12):5951–5956 5953
not the 50-mg dose. Similarly, IGF-binding protein-3 showed
a trend toward lower concentrations after the 25-mg dose
(⫺7 ⫾ 13%; P ⫽ 0.09), but not the 50-mg dose. There were no
changes in circulating serum triglycerides, cholesterol, or
LDL or HDL cholesterol concentrations with either dose of
exemestane. Table 2 summarizes the results of the hormonal
and lipid data.
Study II: PK
As the level of suppression of circulating estrogens was
comparable between doses, we elected to use 25 mg for the
subsequent PK study. In all individuals, the highest concen-
trations of exemestane were observed in the first blood sam-
ple drawn 1 h after oral administration, indicating rapid
absorption of the drug. Plasma concentration vs. time profiles
 5954 J Clin Endocrinol Metab, December 2003, 88(12):5951–5956 Mauras et al. • Pharmacokinetics of Exemestane in Males

TABLE 2. Changes in hormone and lipid concentrations in study I: young male subjects received 25 or 50 mg exemestane daily for 10
days

End of 10-d % Change from

Dose Baseline P value
Assay n treatment baseline
(mg) (mean ⫾ SD) (end ⫺ baseline)
(mean ⫾ SD) (mean ⫾ SD)
Free testosterone (ng/dl) 25 11 9.5 ⫾ 3.3 19.1 ⫾ 4.7 117.0 ⫾ 73.9 0.0001
50 10 8.2 ⫾ 2.9 19.4 ⫾ 4.5 153.6 ⫾ 94.6 0.0000
DHEAS (ng/ml) 25 11 1561 ⫾ 826 1662 ⫾ 726 18.6 ⫾ 39.9 0.4227
50 9 1771 ⫾ 909 1876 ⫾ 840 2.8 ⫾ 12.5 0.7804
Cortisol (␮g/dl) 25 9 10.2 ⫾ 3.4 13.1 ⫾ 2.7 37.9 ⫾ 39.5 0.0080
50 9 11.8 ⫾ 6.6 11.3 ⫾ 3.5 34.2 ⫾ 104.0 0.7781
SHBG (nmol/liter) 25 10 22 ⫾ 7 18 ⫾ 5 ⫺20.6 ⫾ 7.0 0.0003
50 10 28 ⫾ 20 19 ⫾ 5 ⫺18.9 ⫾ 39.2 0.1756
IGF-I (ng/ml) 25 11 533 ⫾ 137 455 ⫾ 80 ⫺12.5 ⫾ 11.1 0.0075
50 10 491 ⫾ 149 471 ⫾ 118 2.0 ⫾ 19.4 0.8197
IGFBP-3 (ng/liter) 25 11 5.0 ⫾ 0.9 4.6 ⫾ 0.6 ⫺7.0 ⫾ 12.5 0.0878
50 10 4.8 ⫾ 0.5 4.7 ⫾ 0.6 0.2 ⫾ 8.1 0.9776
Triglycerides (mg/dl) 25 11 89.9 ⫾ 57.8 86.2 ⫾ 49.4 ⫺0.8 ⫾ 26.4 0.5821
50 10 118.5 ⫾ 145.1 93.6 ⫾ 51.1 28.0 ⫾ 60.3 0.5634
Cholesterol (mg/dl) 25 11 144 ⫾ 11 142 ⫾ 17 ⫺1.3 ⫾ 9.3 0.6513
50 10 139 ⫾ 15 145 ⫾ 14 4.2 ⫾ 6.3 0.0725
Cholesterol HDL (mg/dl) 25 11 42 ⫾ 11 42 ⫾ 12 ⫺1.0 ⫾ 7.4 0.6938
50 10 43 ⫾ 11 41 ⫾ 11 ⫺4.1 ⫾ 13.0 0.2796
Cholesterol LDL (mg/dl) 25 11 107 ⫾ 16 106 ⫾ 15 0.4 ⫾ 15.6 0.8423
50 10 96 ⫾ 25 108 ⫾ 13 20.7 ⫾ 48.1 0.1381
DHEAS, Dehydroepiandrosterone sulfate; IGFBP-3, IGF-binding protein-3. To convert to Systeme International units: free testosterone,
nmol/liter (⫻0.03467); DHEAS, ␮mol/liter (⫻0.002714); cortisol, nmol/liter (⫻27.59); IGF-I, mg/liter (⫻1); triglycerides, mmol/liter (⫻0.01129);
cholesterol, mmol/liter (⫻0.02586).

FIG. 2. Mean ⫾ SD exemestane plasma concen-

trations vs. time in 10 young males receiving a
single 25-mg oral dose.

in all subjects were characterized by a biexponential decline
in exemestane (Fig. 2), with terminal half-life of 8.9 h. The
other PK parameters are listed in Table 3. The mean maximal
plasma concentration of the metabolite 17-hydroexemestane
was 1.16 ⫾ 0.36 ng/ml, a concentration achieved 1 h after the
exemestane dose. These levels rapidly declined, and con-
centrations below the lower limit of sensitivity (0.1 ng/ml)
were observed at a median time of 12 h (range, 4 –24 h).
The mean baseline levels of estradiol and testosterone
were 24.5 ⫾ 8.8 pg/ml and 581 ⫾ 165 ng/dl, respectively.
Maximal suppression of estradiol (62 ⫾ 14%) was observed
12 h after a single 25-mg dose of exemestane. Estradiol re-
mained suppressed by 58 ⫾ 21% at 24 h and returned to
baseline 3– 6 d after treatment (Fig. 3). At the time of maximal
estradiol suppression, plasma testosterone levels were un-
changed and thereafter tended to increase by 32% between
2–3 d; however, contrary to the significant increase in tes-
tosterone observed after 10-d daily dosing, this change did
not achieve statistical significance after a single oral dose.
Serum LH and FSH concentrations were measured up to 24 h
at the same time intervals as the exemestane samples for the
PK analysis. The mean baseline levels of LH and FSH were
4.8 ⫾ 2.2 and 1.3 ⫾ 0.7 mIU/ml, respectively. The percent
change from baseline up to 24 h is reported in Fig. 4. The LH
levels initially decreased by 26% at 2 h; thereafter, there was
a tendency for an increase to a maximum of 81% at 24 h. The
levels of FSH were unchanged up to 12 h and increased by
49% at 24 h.

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 Mauras et al. • Pharmacokinetics of Exemestane in Males
TABLE 3. Pharmacokinetic parameters after a single 25-mg oral
dose of exemestane in 10 young males
PK parameter Mean ⫾ SE
Cmax (ng/ml) 16.1 ⫾ 8.0
AUC (ng/ml䡠h) 36.4 ⫾ 8.8
Kel (h⫺1) 0.0955 ⫾ 0.0363
Half-life (h) 8.9 ⫾ 5.3
MRT (h) 7.0 ⫾ 3.7
Oral clearance (liter/h) 725 ⫾ 186
Cmax, Maximum plasma concentration; Kel, slope of the regres-
sion line; MRT, mean residence time.
FIG. 3. Percent change from baseline (mean ⫾ SD) in plasma estradiol
concentrations after a single 25-mg dose of exemestane in 10 young
males.
Safety
Exemestane was well tolerated by the study subjects, with
no serious adverse events reported. General chemistries,
CBC, and differential urinalysis and liver profiles were mea-
sured and were unchanged during administration.
Discussion
We report the first detailed study of the pharmacological
effects of exemestane in male subjects. Doses of 25 and 50 mg
were comparable in suppressing all circulating estrogens and
had similar effects of increasing serum androstenedione and
testosterone concentrations. There were 38%, 71%, and 45%
decreases in estradiol, estrone, and estrone sulfate concen-
trations, respectively, after 10 d, approximately 24 h after
administration of the last dose of 25 mg exemestane, coupled
with 60% and 32% increases in testosterone and andro-
stenedione concentrations. The rise in the aromatase sub-
strates, testosterone and androstenedione, is probably sec-
ondary to substrate accumulation and/or to the feedback
increase in gonadotropins caused by aromatase blockade.
The 21% decrease in SHBG concentrations caused by 25 mg
exemestane confirms the observation in postmenopausal
women (20).
The maximum plasma concentration, time to achieve max-
imal concentrations and oral clearance for exemestane after
oral administration of a single dose of 25 mg in the present
study of males were similar to those reported for females
(21–23). The terminal half-life in the present study (8.9 h) was
considerably shorter than the published value of 27 h (23).
The reason for this difference is not clear, but may be related
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J Clin Endocrinol Metab, December 2003, 88(12):5951–5956 5955
FIG. 4. Percent change from baseline (mean ⫾ SD) in plasma LH and
FSH concentrations after a single 25-mg dose of exemestane in 10
young males.
to a true gender dependency possibly involving the volume
of distribution (lower in males than females) and plasma or
tissue protein binding (respectively, higher and lower in
males). This finding may also be due to the lower sensitivity
of the analytical methodology used in the previous studies
(14 pg/ml by HPLC/RIA) (21).
The maximal suppression evoked by exemestane at the
single dose of 25 mg in the present study was similar to
published results in postmenopausal women, but the time
course differed (24). Evans et al. (24) reported that a single
25-mg oral dose of exemestane maximally suppressed estra-
diol concentrations by 72% 3 d after administration, and
estradiol levels returned to baseline only 8 –11 d after drug
administration. In the present study maximal suppression of
estradiol of 62% was observed 12 h after exemestane admin-
istration and returned to baseline 3– 6 d after administration.
The reason for this difference is not clear, but may be related
to the shorter half-life of exemestane in males, the lower
exposure to exemestane, and the higher levels of the aro-
matase substrates androstenedione (⬃1 ng/ml in young
males vs. ⬃0.5 ng/ml in postmenopausal women), particu-
larly the much higher testosterone concentrations in young
males than in postmenopausal women (⬃700 ng/dl vs. ⬃20
ng/dl, respectively) (25). This is supported by the observa-
tion that in the 10-d study in young males reported here, the
suppression of estradiol is weaker (due to the very high
levels of the precursor testosterone) than that of estrone (due
to androstenedione levels not very different from those in
postmenopausal women). A limited suppression of circulat-
ing estradiol (⬃50%) has been reported in a similar study in
young males treated with 1 mg daily anastrozole (7), a dose
that reduces estradiol by 85% in postmenopausal women
(23).
Aromatase inhibitors are being investigated in a variety of
clinical situations besides breast cancer. As estrogen is the
principal factor responsible for epiphyseal fusion, aromatase
blockers are being studied in the treatment of severe short
stature in boys (8, 9). This class of compounds has a theo-
retical advantage over using LHRH analogs to delay puberty,
because they allow for progressive virilization while de-
creasing estrogens, potentially extending the time of epiph-
yseal fusion and thus the time for linear growth. Trials have
not yet been performed in adolescent females due to the
concerns that increased circulating gonadotropins, de-
creased estrogens, and increased testosterone could precip-
 5956 J Clin Endocrinol Metab, December 2003, 88(12):5951–5956
itate ovarian dysfunction and virilization, as is seen in the
aromatase-deficient female (3, 26). Because of its properties
of increasing circulating gonadotropins, it has been used as
a treatment for oligospermic men with low testosterone/
estradiol ratios with initial preliminary success (27). This
class of compounds also has a theoretical application in the
treatment of gynecomastia in those individuals with over-
expressed aromatase activity as recently reported (28). In
addition, studies conducted using estrogen receptor block-
ade in the treatment of gonadotropin-independent preco-
cious puberty have shown encouraging results (29); hence,
the use of aromatase blockers seems like a natural alternative
worthy of clinical trials as well.
We conclude that exemestane is a potent aromatase in-
hibitor in men. Exemestane appears to be an alternative in the
choice of inhibitors of the aromatase enzyme available for
human studies. Further studies are underway to estimate
dose and dosing intervals that will provide therapeutic sup-
pression of estrogen concentrations in males. Long-term
safety will also require further investigation.
Acknowledgments
We are grateful to Burnese Rutledge and the nursing staff of Wolfson
Children’s Hospital Clinical Research Center, to Brenda Sager and the
Biomedical Analysis Laboratory, and to Steve Fordham and Holly
Murphy.
Received July 23, 2003. Accepted September 10, 2003.
Address all correspondence and requests for reprints to: Nelly Mau-
ras, M.D., Nemours Children’s Clinic, 807 Children’s Way, Jacksonville,
Florida 32207. E-mail: nmauras@nemours.org.
This work was supported by a grant from Amersham Pharmacia
Biotech.
References
1. Smith EP, Boyd J, Frank GR, Takahashi H, Cohen RM, Specker B, Williams
TC, Lybahn DB, Korach, KS 1994 Estrogen resistance caused by a mutation
in the estrogen-receptor gene in a man. N Engl J Med 331:1056 –1061
2. Carani C, Qin K, Simoni M, Faustini-Fustini M, Serpente S, Boyd J, Korach
KS, Simpson ER 1997 Effect of testosterone and estradiol in man with aro-
matase deficiency. N Engl J Med 337:95
3. Morishima A, Grumbach MM, Simpson ER, Fisher C, Qin K 1995 Aromatase
deficiency in male and female siblings caused by a novel mutation and the
physiological role of estrogens. J Clin Endocrinol Metab 80:3689 –3698
4. Simpson ER 1998 Genetic mutations resulting in estrogen insufficiency in the
male. Mol Cell Endocrinol 145:55–59
5. Fisher CR, Graves KH, Parlow AF, Simpson ER 1998 Characterization of mice
deficient in aromatase (ArKO) because of targeted disruption of the cyp19
gene. Proc Natl Acad Sci USA 95:6965– 6970
6. Hewitt SC, Korach KS 2002 Estrogen receptors: structure, mechanisms and
function. Rev Endocr Metab Disord 3193–3200
7. Mauras N, O’Brien KO, Oerter Klein K, Hayes V 2000 Estrogen suppression
in males: metabolic effects. J Clin Endocrinol Metab 85:2370 –2377
8. Wickman S, Sipila I, Ankarberg-Lindgren C, Norjavaara E, Dunkel L 2001
A specific aromatase inhibitor and potential increase in adult height in boys
with delayed puberty: a randomized controlled trial. Lancet 357:1743–1748
9. Mauras N, Rini A, Welch S, Oerter-Klein K, Long term effects of combined
treatment with an aromatase blocker (Arimidex®) and GH in GH deficient
Downloaded from https://academic.oup.com/jcem/article-abstract/88/12/5951/2661508
by guest
on 28 February 2018
Mauras et al. • Pharmacokinetics of Exemestane in Males
(GHD) boys in puberty: preliminary results [Abstract OR-9-99]. LWPES/ESPE
6th Joint Meeting of the Society for Pediatr Research, Montréal, Canada, 2001
10. Simpson ER, Zhao Y, Agarwal VR, Michael MD, Bulun SE, Hinshelwood
MM, Graham-Lorence S, Sun T, Fisher CR, Qin K, Mendelson CR 1997
Aromatase expression in health and disease. Recent Prog Horm Res 52:185–
214
11. Sasano H, Uzuki M, Sawai T, Nagura H, Matsunaga G, Kashimoto O, Harada
N 1997 Aromatase in human bone tissue. J Bone Miner Res 12:1416 –1423
12. Clemett D, Lamb HM 2000 Exemestane: a review of its use in postmenopausal
women with advanced breast cancer. Drugs 59:1279 –1296
13. 2003 Aromasin. In: Physicians desk reference, 57th ed. Montvale, NJ: Thomson
PDR; 2692–2695
14. Lonning PE, Bajetta E, Murray R, Tubiana-Hulin M, Eisenberg PD, Mick-
iewicz E, Celio L, Pitt P, Mita M, Aaronson NK, Fowst C, Arkhipov A, di Salle
E, Polli A, Massimini G 2000 Activity of exemestane in metastatic breast
cancer after failure of non steroidal aromatase inhibitors: a phase II trial. J Clin
Oncol 18:2234 –2244
15. Kaufmann M, Bajetta E, Dirix LY, Fein LE, Jones SE, Zilembo N, Dugardyn
JL, Nasurdi C, Mennel RG, Cervek J, Fowst C, Polli A, di Salle E, Arkhipov
A, Piscitelli G, Miller LL, Massimini G 2000 Exemestane is superior to
megestrol acetate after tamoxifen failure in postmenopausal women with
advanced breast cancer: results of a phase III randomized double-blind trial.
J Clin Oncol 18:1399 –1411
16. Johannessen DC, Engan T, Di Salle E, Zurlo MG, Paolini J, Ornati G,
Piscitelli G, Kvinnsland S, Lonning PE 1997 Endocrine and clinical effects of
exemestane (PNU 155971), a novel steroidal aromatase inhibitor, in postmeno-
pausal breast cancer patients: a phase I study. Clin Cancer Res 3:1101–1108
17. Cenacchi V, Barattč S, Cicioni P, Frigerio E, Long J, James C 2000 LC-MS-MS
determination of exemestane in human plasma with heated nebulizer interface
following solid-phase extraction in the 96 well plate format. J Pharmacol Biom
Anal 22:451– 460
18. Hills M, Armitage P 1979 The two-period cross-over clinical trial. Br J Clin
Pharmacol 8:7–20
19. Gibaldi M, Perrier D 1982 Pharmacokinetics, 2nd Ed. New York: Marcel
Dekker
20. Zilembo N, Noberasco C, Bajetta E, Martinetti A, Mariani L, Orefice S,
Buzzoni R, Di Bartolomeo M, Di Leo A, Laffranchi A 1995 Endocrinological
and clinical evaluation of exemestane, a new steroidal aromatase inhibitor. Br J
Cancer 72:1007–1012
21. Poggesi I, Jannuzzo MG, di Salle E, Piscitelli G, Rocchetti M, Spinelli R,
Broutin F, Ornati G, Massimini G 1999 Effect of food and formulation on the
pharmacokinetics (PK) and pharmacodynamics (PD) of a single oral dose of
exemestane (Aromasin®, EXE) [Abstract 741]. Proc Am Soc Clin Oncol 18:193a
22. Spinelli R, Jannuzzo MG, Poggesi I 1999 Pharmacokinetics (PK) of Aromasin
(Exemestane, EXE) after single and repeated doses in healthy postmenopausal
volunteers (HPV) [Abstract 1185]. Eur J Cancer 35:S295
23. Buzdar AU, Robertson JFR, Eiermann W, Nabholtz JM 2002 An overview of
the pharmacology and pharmacokinetics of the newer generation aromatase
inhibitors anastrozole, letrozole and exemestane. Cancer 95:2006 –2016
24. Evans TR, Di Salle E, Ornati G, Lassus M, Benedetti MS, Pianezzola E,
Coombes RC 1992 Phase I and endocrine study of exemestane (FCE 24304), a
new aromatase inhibitor in postmenopausal women. Cancer Res 52:5933–5939
25. Kvinnsland S, Anker G, Dirix LY, Bonneterre J, Prove AM, Wilking N,
Lobelle JP, Mariani O, di Salle E, Polli A, Massimini G 2000 High activity
and tolerability demonstrated for exemestane in postmenopausal women with
metastatic breast cancer who had previously failed on tamoxifen treatment.
Eur J Cancer 36:976 –982
26. Mullis PE, Yoshimura N, Kuhlmann B, Lippuner K, Jaeger P, Harada H 1997
Aromatase deficiency in a female who is compound heterozygote for two new
point mutations in the P450arom gene: impact of estrogens on hypergonado-
tropic hypogonadism, multicystic ovaries, and bone densitometry in child-
hood. J Clin Endocrinol Metab 82:1739 –1745
27. Raman JD, Schlegel PN 2002 Aromatase inhibitors for male infertility. J Urol
167:624 – 629
28. Shozu M, Sebastian S, Takayama K, Hsu WT, Schultz RA, Neely K, Bryant
M, Bulun SE 2003 Estrogen excess associated with novel gain-of-function
mutations affecting the aromatase gene. N Engl J Med 348:1855–1865
29. Eugster E, Rubin S, Reiter E, Plourde P, Jou HC, Pescovitz O 2003 Tamoxifen
treatment for precocious puberty (PP) in McCune-Albright syndrome: mul-
ticenter trial. J Pediatr 143:60 – 66